Pyrazolopyridine derivatives and their use in treating inflammation and allergic conditions

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof: ##STR1## wherein: X is NR wherein R is hydrogen or C 1-6  alkyl, oxygen, sulphur, SO or SO 2  ; 
     R 1  is COR 5  wherein R 5  is hydroxy, or COR 5  is a pharmaceutically acceptable ester or amide group; or CF 3  ; and R 2  is hydrogen, C 1-6  alkyl or phenyl optionally substituted by halogen, CF 3 , C 1-4  alkoxy or C 1-4  alkyl; or R 2  is COR 5  as defined or CF 3  and R 1  is hydrogen; 
     R 3  is C 1-10  alkyl, optionally substituted by hydroxy, C 1-4  alkoxy, thiol, C 1-4  alkylthio or NR 6  R 7  wherein R 6  and R 7  are independently hydrogen or C 1-6  alkyl or together are C 3-6  polymethylene; C 2-10  alkenyl or phenyl optionally substituted by one or two of halogen, CF 3 , C 1-4  alkoxy, C 1-4  alkyl, hydroxy, nitro, cyano, C 2-10  acyloxy, NR 8  R 9  wherein R 8  and R 9  are independently selected from hydrogen, C 1-6  alkyl, C 2-7  alkanoyl or C 1-6  alkylsulphonyl or COR 10  wherein R 10  is hydroxy, C 1-6  alkoxy or NR 11  R 12  wherein R 11  and R 12  are independently selected from hydrogen or C 1-6  alkyl; and 
     R 4  is hydrogen; or C 1-4  alkyl or benzyl attached at nitrogen atom 1 or 2 having anti-inflammatory and/or anti-allergy activity, a process for their preparation and their use as pharmaceuticals.

The present invention relates to pyrazolopyridines having usefulpharmacological activity, to a process for their preparation and totheir use as anti-inflammatories.

J. Heterocycl. Chem. 1971, 8(6), 1035-7 discloses compounds of theformula (A): ##STR2## wherein R is NH₂, OH, NAc₂ or Cl. The compoundwherein R is NAc₂ is described as having CNS antidepressant activity inmice.

A structurally distinct group of pyrazolopyridine derivatives have nowbeen discovered which compounds have anti-inflammatory (includinganti-rheumatic) and/or anti-allergy activity.

Accordingly, the present invention provides a compound of the formula(I) and pharmaceutically acceptable salts thereof: ##STR3## wherein: Xis NR wherein R is hydrogen or C₁₋₆ alkyl, oxygen, sulphur, SO or SO₂ ;

R₁ is COR₅ wherein R₅ is hydroxy, or COR₅ is a pharmaceuticallyacceptable ester or amide group; or CF₃ ; and R₂ is hydrogen, C₁₋₆ alkylor phenyl optionally substituted by halogen, CF₃, C₁₋₆ alkoxy or C₁₋₄alkyl; or R₂ is COR₅ as defined or CF₃ and R₁ is hydrogen;

R₃ is C₁₋₁₀ alkyl, optionally substituted by hydroxy, C₁₋₄ alkoxy,thiol, C₁₋₄ alkylthio or NR₆ R₇ wherein R₆ and R₇ are independentlyhydrogen or C₁₋₆ alkyl or together are C₃₋₆ polymethylene C₂₋₁₀ alkenylor phenyl optionally substituted by one or two of halogen, CF₃, C₁₋₄alkoxy, C₁₋₄ alkyl, hydroxy, nitro, cyano, C₂₋₁₀ acyloxy, NR₈ R₉ whereinR₈ and R₉ are independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₇alkanoyl or C₁₋₆ alkylsulphonyl or COR₁₀ wherein R₁₀ is hydroxy, C₁₋₆alkoxy or NR₁₁ R₁₂ wherein R₁₁ and R₁₂ are independently selected fromhydrogen or C₁₋₆ alkyl; and

R₄ is hydrogen; or C₁₋₄ alkyl or benzyl attached at nitrogen atom 1 or2.

Suitable values for X include those wherein R in NR is hydrogen, methyl,ethyl, n- and iso-propyl, preferably hydrogen; and oxygen or sulphur.Favourably X is NH.

Suitable values for R₁ /R₂ when COR₅ include COR₅ ¹ wherein R₅ ¹ ishydroxy, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, phenoxy or benzyloxy wherein thephenyl/benzyl moiety is optionally substituted by one or two of halogen,CF₃, C₁₋₄ alkoxy and C₁₋₄ alkyl; or R₅ ¹ is NR₁₃ R₁₄ wherein R₁₃ and R₁₄are independently hydrogen, C₂₋₆ alkyl, C₂₋₆ alkenyl, benzyl or phenyloptionally substituted as described above.

Examples of R₅ ¹ include hydroxy, methoxy, ethoxy, n- or iso-propoxy,amino, methylamino, dimethylamino, anilino and allylamino.

Suitable values for R₂ when other than COR₅ include hydrogen, methyl,ethyl, n- and iso-propyl and phenyl. Preferably R₂ is then hydrogen ormethyl, usually hydrogen.

Preferably R₁ is COR₅.

Suitable values for R₃ include methyl, ethyl, n- and iso-propyl, n-,iso- sec- and tert-butyl, n-pentyl or (CH₂)nCH₃ wherein n is 4 to 7,optionally substituted by methyl, ethyl and/or hydroxy, methoxy, n- oriso-propoxy, thiol, methylthio or amino optionally substituted by one ortwo methyl groups or by C₄ or C₅ polymethylene, vinyl, prop-1-enyl,prop-2-enyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-3-enyl,1-methylenepropyl, 1-methylprop-1-enyl and 1-methylprop-2-enyl in theirE and Z forms where stereoisomerism exists; or phenyl optionallysubstituted by one or two chloro, bromo, methoxy, ethoxy, n- andiso-propoxy, methyl, ethyl, n- and iso-propyl, n-, iso- sec- andtert-butyl, hydroxy, nitro, cyano, acetoxy, propionyloxy, benzyloxy, NR₈¹ R₉ ¹ wherein R₈ ¹ and R₉ ¹ are independently selected from hydrogen,methyl, ethyl, n- and iso-propyl, acetyl, propionyl, methylsulphonyl andethylsulphonyl; COR₁₀ ¹ wherein R₁₀ ¹ is hydroxy, methoxy, ethoxy, orNR₁₁ ¹ R₁₂ ¹ wherein R₁₁ ¹ and R₁₂ ¹ are independently selected fromhydrogen, methyl, n- and iso-propyl. Favourable values for R₃ includen-butyl, n pentyl, allyl, 2-methylallyl, 2-hydroxyethyl,3-hydroxypropyl, 2-dimethylamino ethyl, 3-dimethylaminopropyl, phenyland phenyl substituted by one of hydroxy, nitro, cyano, carboxy, t-butyland ethoxycarbonyl in the 3- or 4-position.

Suitable values for R₄ include hydrogen, methyl, ethyl, n- andiso-propyl and benzyl. More suitably R₄ is hydrogen or 2-methyl.Favourably R₄ is hydrogen.

It will be appreciated that when R₄ is hydrogen the compounds of formula(I) exist as tautomers, i.e. the R₄ hydrogen atom is labile. Thecompounds wherein R₄ is hydrogen are therefore of formulae (IIa) and(IIb). ##STR4##

The compounds of the formula (I) can form acid addition salts withacids, such as the conventional pharmaceutically acceptable acids, forexample hydrochloric, hydrobromic, phosphoric, acetic, fumaricsalicylic, citric, lactic, mandelic, tartaric and methanesulphonic.

There is a group of compounds within formula (I) wherein either R₁ ishydrogen and R₂ is COR₅ ' wherein R₅ ' is hydroxy, C₁₋₆ alkoxy or NR₁₃'R₁₄ ' wherein R₁₃ ' and R₁₄ ' are independently C₁₋₆ alkyl; or CF₃ orR₁ is COR₅ ' or CF₃ and R₂ is hydrogen, R₃ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenylor phenyl optionally substituted as defined in formula (I), R₄ whenother than hydrogen is attached at nitrogen atom 2 and the remainingvariables are as defined in formula (I).

There is a favourable group of compounds within formula (I) of formula(III): ##STR5## wherein R₁ ¹ is COR₅ ¹ as defined or CF₃, R40 ishydrogen or methyl, R₄ ¹ is hydrogen or 2-methyl, and R₃ is as definedin formula (I).

Suitable and preferred values for R₁ ¹, R', R₄ ¹ and R₃ are as describedfor the relevant variables under formula (I).

A favourable sub-group of compounds within formula (III) is of formula(IV): ##STR6## wherein R₁₅ is hydrogen, chloro, bromo, methoxy, ethoxy,hydroxy, cyano, carboxyl, ethoxycarbonyl, nitro or t-butyl.

Preferably R₁₅ when other than hydrogen is attached at the the 3- or4-position, most preferably the 4-position.

A preferred sub-group of compounds within formula (III) is of formula(V): ##STR7## wherein R₃ ¹ is n-butyl, n-pentyl, allyl, 2-methylallyl,2-hydroxyethyl, 3-hydroxypropyl, 2-thiolethyl, 2-methoxyethyl,2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-pyrrolidinoethyl or3-pyrrolidinopropyl and R₁ ¹ and R₄ ¹ are as defined in formula (III).

Suitable and preferred values for the variables are as described for therelevant variables under formula (I).

A further group of compounds within formula (I) is of formula (VI):##STR8## wherein R₂ ¹ is COR₅ ¹ as defined and the remaining variablesare as defined in formula (III).

Suitable and preferred values for R₂ ¹, R', R₃ and R₄ ¹ are as describedfor the relevant variables under formula (I).

A preferred sub-group of compounds within formula (VI) is of formula(VII): ##STR9## wherein R₃ ¹ and R₄ ¹ are as defined in formula (V) andR₂ ¹ is as defined in formula (VI).

Suitable and preferred values for the variables are as described for therelevant variables under formula (I).

Another sub-group of compounds within formula (I) is of formula (VIII):##STR10## wherein X¹ is oxygen or sulphur, and R₁ ¹, R₃ and R₄ ¹ are asdefined in formula (III).

Suitable and preferred values for X¹, R₁ ¹, R₃ and R₄ ¹ are as describedfor the relevant variables under formula (I).

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises the reaction of a compound of formula (IX):##STR11## wherein Q is a leaving group, R₁ ' and R₂ ' are R₁ and R₂ orgroups convertible thereto and R₄ is as defined in formula (I), with acompound of formula (X):

    HX.sup.2 R.sub.3 '                                         (X)

wherein X² is NR (as defined in formula (I)), oxygen or sulphur and R₃ 'is R₃ or a group or atom convertible thereto; and thereafter optionallyconverting X² to X, R₁ ' to R₁, R₂ ' to R₂, R₃ ' to R₃ and/or an R₄hydrogen to an R₄ C₁₋₆ alkyl group and/or forming a pharmaceuticallyacceptable salt thereof.

Suitable leaving groups Q include halogens such as chloro and bromo,preferably chloro.

The reaction may be carried out under conventional conditions fornucleophilic aromatic displacements, at elevated temperatures usingexcess of reagent as solvent (eg aniline when X is NR) or in an inertsolvent such as toluene, ethanol, dimethylformamide, dimethylsulphoxide,dioxan or water. The reaction preferably takes place in a sealed tube ifHX₂ R₃ ' is of low boiling point.

Alternatively, when X² is oxygen or sulphur, the reaction may take placein the presence of a base, such as sodium hydride, potassium t-butoxideor sodium t-butoxide.

Compounds of formula (I) wherein X is SO or SO₂ may be prepared from thecorresponding compounds wherein X is S by conventional oxidationmethods, such as using sodium periodate or with one equivalent ofm-chloroperbenzoic acid (to form the compound of formula (I) wherein Xis SO) or two equivalents of m-chloroperbenzoic acid (to form thecompound of formula (I) wherein X is SO₂).

Conversion of an R hydrogen in X to an R C₁₋₆ alkyl group may be carriedout by conventional amine alkylation or acylation (e.g. formylation)followed by reduction.

An R₅ hydroxy group in R₁ or R₂ may be converted to an R₅ alkoxy groupby conventional esterification procedures and an R₅ hydroxy group may beconverted to an NR₆ R₇ group by condensation and in the presence of adehydrating agent, such as dicyclohexylcarbodiimide.

An COR₅ group when amide can be converted to a COR₅ ester group byconventional hydrolysis/esterification in ethanolic HCl. One COR₅ estergroup may be converted to another COR₅ ester by conventionaltransesterification procedures. It will be appreciated that when R₂ isan ester group, reaction of the compound of formula (X) with thecompound of formula (IX) may also substitute R₅, in which casesubsequent conversion of R₅ is necessary as described above.

R₁ ' or R₂ ' may be methyl, in which case it may be converted to a CO₂ Hgroup by conventional oxidation with an oxidising agent such aspotassium permanganate. This conversion is preferably, however, carriedout on the intermediate of formula (V) or at an earlier stage.

Conversions of R₃ phenyl substituents are generally known in the art ofaromatic chemistry. Examples of such conversions are as follows:

(a) an hydroxy group may be converted to acyloxy by conventionalacylation procedures, preferably using the acid anhydride intrifluoroacetic acid at elevated temperature;

(b) a cyano group may be converted to carboxy by base catalysedhydrolysis; preferably using sodium hydroxide in ethanol followed byneutralisation with acid.

(c) an alkoxycarbonyl group may be converted to CONR₁₀ R₁₁ by heatingwith the appropriate amine;

(d) a nitro group may be converted to an amino group by reduction,preferably by catalytic reduction using palladium on charcoal;

(e) an amino group may be converted to an alkylamino or acylamino groupby conventional amine acylation or alkylation; the acylation ispreferably carried out using an acid anhydride and the alkylation usingthe alkyl halide;

(f) an amino group may be converted to an alkylsulphonyl group byreaction with the appropriate alkylsulphonyl chloride, preferably usingan acid acceptor such as triethylamine in an inert solvent such asdichloromethane.

An R₄ hydrogen atom may be converted to an R₄ C₁₋₆ alkyl group byconventional alkylation procedures.

It will be appreciated that these conversions may take place in anydesired or necessary order. Conversions involving amine substitution mayalso substitute an R₄ hydrogen which therefore may need to be protectedusing an amine protecting group.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid.

Compounds of the formula (IX) are either known compounds or can beprepared by analogy with processes for preparing structurally similarknown compounds.

For example, compounds of the formula (IX) wherein Q is chloro may beprepared by the phosphorus oxychloride chlorination of a compound offormula (XI): ##STR12## Compounds of the formula (X) may be prepared asdescribed in J. Chem. Soc. Perkin Trans. I, 1976 (5), 507 or byanalogous methods thereto.

It will be appreciated that the compounds of formula (XI) wherein R₄ ishydrogen exist in the predominant tautomeric form of formula (XIa):##STR13##

In a further aspect the invention provides a pharmaceutical compositionwhich comprises a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. Thecompositions may be adapted for administration via the topical, oral,rectal or injection routes. The compositions of this invention maycontain diluents, binders, fillers, disintegrants, flavouring agents,colouring agents, lubricants, preservatives in conventional manner.These conventional excipients may be employed in conventional manner,for example as in the preparation of compositions of ketoprofen,indomethacin, naproxen, acetylsalicyclic acid or other anti-inflammatoryagents.

The compounds of the invention have topical anti-inflammatory activityand therefore will normally be made up into a cream, lotion, gel orointment for topical administration to the skin comprising a compound ofthe formula (I) which has been formulated as a cream, lotion, gel orointment.

Cream, lotion, gel or ointment formulations that may be used forcompounds of the formula (I) are conventional formulations well known inthe art, for example, as described in standard text books ofpharmaceutics and cosmetics, such as Harry's Cosmeticology published byLeonard Hill Books, and the British Pharmacopoeia. A standardemulsifying ointment base or anhydrous polyethylene glycol are simpleexamples of such suitable formulations.

Examples of oils suitable for inclusion in a standard emulsifyingointment base include mineral oils, vegetable oils, synthetic fatty acidesters, fatty alcohols, lanolin and its derivatives.

These compositions will normally include a suitable emulsifier. Thecomposition can range from liquid through semi-liquid to gel typesaccording to the type of emulsion and quantity of any thickening agentwhich may be present. Examples of emulsifiers include polyhydric alcoholesters such as sorbitan monostearate, fatty acid esters such as glycerylmonostearate, and polyester derivatives of fatty acids or fattyalcohols.

The compositions may also contain anti-oxidants and other conventionalingredients such as preservatives, perfumes and alcohol. Advantageously,a penetrating agent such as AZONE may also be included.

The compositions for topical treatment may also contain otherthereapeuitic agents such as anti-infective and/or anti-viral agents.Suitable anti-infective agents include the topically applicableantibacterial, anti-yeast, anti-fungal and anti-herpes agents.

These compositions may be used in the topical treatment of atopic andcontact dermatitis, psoriases, acne, eczeme and other inflammatorydermatoses and inflammatory conditions of eyes, ears, nose and throat.Treatment of inflammation of the skin may, however, also be carried oututilising an oral composition of the invention, as hereinbeforedescribed.

It will be appreciated that the amount of compound of the formula (I)used will depend on a number of factors such as the nature and severityof the disorder being treated, and the specific compound being used.However, by way of illustration it is believed that effective therapycan be achieved using roughly similar amounts of the compounds offormula (I) as would be used of hydrocortisone. A typical formulationwill suitably contain 0.1 to 20%, more suitably 0.5 to 5% of thecompound of formula (I).

A composition of this invention is useful in the treatment of rheumatismand arthritis and in the treatment of pain and other inflammatoryconditions and also in the treatment of the propylaxis of bronchialasthma, rhinitis, hay fever and allergic eczema. Suitably the oralcompositions of this invention will be in the form of a unit dose suchas a tablet, capsule or reconstitutable powder in a sachet. Such unitdoses will generally contain from 10 mg to 1000 mg and more suitablywill contain from about 30 mg to 500 mg for example 50 mg to 250 mg ofactive agent, for example about 50, 100, 150, 200, 250, 300, 350, 400,450 or 500 mg. These compositions may be administered once or more timesa day, for example 2, 3 or 4 times daily, so that the total daily dosefor a 70 kg adult will usually be in the range of 20 to 3000 mg and moreusually in the range 40 to 1000 mg. Alternatively the unit dose maycontain from 2-20 mg of active agent and may be administered inmultiples if desired to give the preceeding daily dose.

For use in the treatment or prophylaxis of allergic disorders, in any ofthe preceding formulations, a suitable dosage unit may contain 0.01 to500 mg of active ingredient, more suitably 1 to 500 mg for use via theorgal route, 0.01 to 10 mg via inhalation, which is preferred. Theeffective dose of compound depends on the particular compound employed,the condition of the patient and the frequency and route ofadministration, but in general is in the range of from 0.001 mg/day to100 mg/day per kilogram of the patient's body weight. No adversetoxicological effects are indicated at any of the aforementioned dosageranges.

Where appropriate, small amounts of other anti-asthmatics andbronchodilators, for example sympathomimetic amines such asisoprenaline, isoetharine, slabutamol, phenylephrine and ephedrine;xanthine derivatives such as theophylline and aminophylline andcorticosteroids such as prednisolone and adrenal stimulants such as ACTHmay be included.

A favoured form of oral composition of this invention is a tabletcontaining the active agent. The active agent may be in the form of arecompressed granulate of the active ingredient in intimate mixture witha lubricant such as magnesium stearate, a filler such asmicrocrystalline cellulose and a disintegrant such as sodium starchglycollate.

A particular composition of the invention for inflammatory diseases is ahard gelatin capsule containing the required amount of a compound of theinvention in the form of a powder or granulate in intimate mixture witha lubricant, such as magnesium stearate, a filler, such asmicrocrystalline cellulose, and a disintegrant, such as sodium starchglycollate.

Preparations especially suitable for administration to the respiratorytract include, for example, a snuff, an aerosol, a solution for anebulizer, or a microfine powder for insufflation, alone or incombination with an inert carrier such as lactose. In such a case theparticles of active compound suitably have diameters of less than 50microns, preferably less than 10 microns. For parenteral administration,fluid unit dosage forms are prepared utilising a compound of the formula(I) or pharmaceutically acceptable salt thereof and a sterile vehicle.The compound, depending on the vehicle and concentration used, can beeither suspended or dissolved in the vehicle. In preparing solutions,the compound can be dissolved for injection and filter sterilised beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and bufferingagents are dissolved in the vehicle. Parenteral suspensions are preparedin substantially the same manner, except that the compound is suspendedin the vehicle instead of being dissolved and sterilised by exposure toethylene oxide before suspension in a sterile vehicle. Advantageously, asurfactant or wetting agent is included in the composition to facilitateuniform distribution of the compound.

The invention further provides a method of treatment or prophylaxis ofinflammatory and/or allergic conditions in mammals including man whichcomprises the administration of a compound of formula (I) or apharmaceutically acceptable salt thereof to the sufferer.

The invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use in treatinginflammatory and/or allergic conditions in mammals.

Mmammals which may be thus treated include humans and domestic animalssuch as dogs, cats or horses.

Most suitably the medicament will be administered orally as 1, 3 or 4doses per day at the dose level previously indicated.

The following Examples illustrate the invention and the followingDescriptions illustrate the preparation of intermediate thereto.

DESCRIPTION 1 Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate##STR14##

A solution of ethyl4,7-dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-6-carboxylate¹ inphosphorus oxychloride was heated under reflux for 45 min. Afterremoving excess reagent in vacuo, the residue was made basic withsaturated sodium hydrogen carbonate solution. The precipitated solid waswashed with water, then extracted with ethyl acetate to give the crudetitle compound.

δ (DMSO d₆) 1.4 (3H, t, J=7 Hz), 4.3 (2H, q, J=7 Hz), 8.4 (1H, s), 8.8(1H, s).

A much improved yield (67%) of the title compound was obtained bymaintaining the reaction mixture at 70°-80° C. rather than at refluxtemperature.

DESCRIPTION 2 Diethyl 2-(Pyrazol-4-ylamino)fumarate ##STR15##

A solution of 4-nitropyrazole (8.4 g, 75 mmol) in ethanol (300 ml) washydrogenated over 10% palladium on charcoal (800 mg) for 3.5 h. Themixture was filtered and cooled to 5° C. Diethyl acetylenedicarboxylate(12 ml, 75 mmol) was added dropwise with stirring over 10 min. Thesolvent was removed in vacuo, and column chromatography (SiO₂, 2%methanol/ether) gave the fumarate which was crystallised fromether/pentane to give the title compound as plates (8.22 g, 43%), m.p.69°-71° C.

Found: C, 52.16; H, 6.00; N, 16.46. C₁₁ H₁₅ N₃ O₄ requires C, 52.17; H,5.97; N, 16.59%.

δ (CDCl₃) : 1.15 (3H, t, J=7 Hz), 1.30 (3H, t, J=7 Hz), 4.15 (2H, q, J=7Hz), 4.22 (2H, q, J=7 Hz), 5.25 (1H, s), 7.45 (2H, s), 8.00 (1H, bs),9.25 (1H, bs).

DESCRIPTION 3 Ethyl4,7-dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate ##STR16##

Diethyl 2-(pyrazol-4-ylamino)fumarate (7.74 g, 30 mmol) was added toboiling Dowtherm A (250 ml). The solution was heated under reflux for 10min, and then allowed to cool to room temperature. 60°-80° petrol (250ml) added and the solid was collected and washed well with petrol, togive the title compound as pale yellow needles (5.77 g, 99%), m.p.287°-292° C.

δ (TFAD): 1.60 (3H, t, J=7 Hz), 4.80 (2H, q, J=7 Hz), 8.10 (1H, s), 8.80(2H, s).

Found: C, 52.02; H, 4.41; N, 20.18. C₉ H₉ N₃ O₃ requires: C, 52.17; H,4.38; N, 20.28.

DESCRIPTION 4 Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-5-carboxylate##STR17##

Ethyl 4,7-dihydro-7-oxo-1H-pyrazolo[4,3-b]pyridine-5-carboxylate (5.0 g,24 mmol) was heated under reflux in phosphoryl chloride (50 ml) for 25min. Excess reagent was removed in vacuo and the residue was treatedwith water to give a yellow solid. After neutralisation with 10% sodiumhydroxide solution, the solid was collected and dried to give the titlecompound (4.48 g, 83%), m.p. 276°-279° C. after recrystallisation fromethyl acetate.

δ (DMSO-d₆): 1.40 (3H, t, J=7 Hz), 4.40 (2H, q, J=7 Hz), 8.13 (1H, s),8.67 (1H, s).

Found: C, 47.75; H, 3.32; N, 18.74; Cl, 15.78. C₉ H₈ N₃ O₂ Cl requires:C, 47.91; H, 3.57; N, 18.62; Cl, 15.71.

DESCRIPTION 5 Ethyl7-chloro-2-methyl-pyrazolo[4,3-b]pyridine-6-carboxylate ##STR18##

Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (4.5 g, 0.02mole) and dimethyl formamide demethylacetal² (10 ml, 0.04 mole) in drytoluene (200 ml) were heated together under reflux for 1 h. The solventand excess of reagent were distilled off under reduced pressure to givea brown oil containing two isomers. The 1-methyl³ and 2-methyl isomerswere separated by column chromatography on silica gel with ethyl acetateas eluant to give the title compound as a white crystalline solid m.p.118°-120° C.

δ (CDCl₃): 1.45 (3H, t, J=7 Hz), 4.25 (3H, s,), 4.35 (2H, q, J=7 Hz),8.10 (1H, s), 8.75 (1H, s).

The physical characteristics of the isomeric 1-methyl compound were thesame as the literature³ values.

DESCRIPTION 6 7-Chloro-1H-5-trifluoromethylpyrazolo[4,3-b]pyridine (D6)##STR19##

The title compound was prepared by the method given in Description 1 asa pale yellow solid, m.p. 172°-180° C.

δ (DMSO-d₆) 8.12 (1H, s), 8.17 (1H, s).

Found M+ 220.9968. C₇ H₃ CLF₃ N₃ 220.9967.

EXAMPLE 1 Ethyl 7-anilino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate##STR20##

Ethyl 7-chloro-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate (370 mg, 1.6mmol) was dissolved in aniline (3 ml) and stirred overnight. Theresulting mixture was triturated with 60°-80° petrol, and theprecipitated solid was collected and dissolved in aqueous ethanol. Thesolution was adjusted to pH 8 with saturated sodium hydrogen carbonatesolution, and the precipitated solid was collected to give the titlecompound (310 mg, 67%) m.p. 164°-165° C.

δ(DMSO d₆) 1.3 (3H, t, J=7 Hz), 4.25 (2H, q, J=7 Hz), 7.2 (5H, m), 8.2(1H, s), 8.7 (1H, s), 10.1 (1H, br s).

EXAMPLE 2 Ethyl 7-Allylamino-1H-pyrazolo[4,3-b]-pyridine-6-carboxylate(E2). ##STR21##

Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (2.25 g, 0.01mole) and allylamine (20 ml) were stirred together overnight at roomtemperature. The excess allylamine was removed under reduced pressure.The residue was dissolved in the minimum volume of aqueous ethanol andsufficient 10% sodium carbonate added to give pH 8.

The resulting solid was collected and dried to give a yellow solid,which was recrystallized from ether-pentane with a few drops of methanolto facilitate solubility, to give the title compound as the free base(1.0 g, 42%) m.p. 218°-222° C. (Found: C, 58.32; H, 5.72; N, 22.85. C₁₂H₁₄ N₄ O₂ requires C, 58.53; H, 5.73; N, 22.75%)

δ(CDCl₃) 1.4 (3H, t, J=7 Hz), 4.3 (2H, q, J=7 Hz), 4.7-4.85 (2H, m),5.05-5.5 (2H, m), 5.75-6.41 (1H, m), 8.15 (1H, s), 8.8 (1H, s).

EXAMPLE 3 Ethyl7-(4-Hydroxyanilino)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (E3)##STR22##

Ethyl 7-chloro-1H pyrazolo[4,3-b]pyridine-6-carboxylate (1.0 g, 0.004mole) and p-aminophenol (1.0 g, 0.009 mole) were stirred together inethyl acetate (200 ml) under nitrogen for 48 hours, the temperaturebeing maintained between -10° and -5° C. The ethyl acetate was removedunder reduced pressure to give a yellow solid. This solid was dissolvedin aqueous ethanol and the pH adjusted to pH8 with 10% sodium carbonatesolution. The resulting solid was filtered off washed with water anddried. Recrystallization from methanol/ethyl acetate gave the titlecompound as a pale yellow solid (650 mg, 50%), m.p. 286°-287° C.(decomposition)

(Found: C, 60.28; H, 4.97; N, 18.70. C₁₅ H₁₄ N₄ O₃ requires C, 60.40; H,4.73; N, 18.78%).

δ (DMSO-d₆) 1.45 (3H, t, J=7 Hz), 4.3 (2H, q, J=7 Hz), 6.75 (2H, d, J=4Hz), 7.11 (2H, d, J=4 Hz), 8.20 (1H, s), 8.71 (1H, s).

EXAMPLE 4 Ethyl 7-Amylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate(E4) ##STR23##

The above compound was prepared from ethyl7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and n-amylamine in ananalogous manner to the preparation of Example 2 giving a pale yellowsolid, m.p. 153°-155° C.

δ(CDCl₃) 0.7-1.8 (6H, m), 1.4 (2H, t, J=7 Hz), 1.9 (3H, s), 3.7-4.0 (2H,m), 4.3 (2H, q, J=7 Hz), 8.0 (1H, s), 8.75 (1H, s).

EXAMPLE 5 Ethyl 7-Phenylthio-1H-pyrazolo[4,3-b]pyridine-6-carboxylate(E5) ##STR24##

The above compound was prepared from ethyl7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate and thiophenol in ananalogous manner to the preparation of Example 1 giving a white solid,m.p. 130°-131° C.

Found: C, 60.09; H, 4.52; N, 13.96; C₁₅ H₁₃ N₃ SO₂ requires C, 60.18; H,4.38; N, 14.04%).

δ (CDCl₃) 1.48 (3H, t, J=7 Hz), 4.5 (2H, q, J=7 Hz), 7.35-7.85 (5H m,),8.28 (1H, s), 9.05 (1H, s).

EXAMPLE 6 Ethyl 7-n-Butylamino-1H-pyrazolo[4,3-b]pyridine-6-carbosylate(E6) ##STR25##

Ethyl 7-chloro-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (3.5 g, 15.5mmol) was dissolved in n-butylamine (25 ml) and stirred at roomtemperature for 3 h. Excess butylamine was removed in vacuo and theresidual solid was washed well with water, and recrystallised from ethylacetate to give the title compound (2.75 g, 67%), m.p. 164°-170° C.

Found: C, 59.04; H, 6.91; N, 21.19; C₁₃ H₁₈ N₄ O₂ requires C, 59.53; H,6.92; N, 21.36.

δ (DMSO-d6) 0.95 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.2-1.8 (4H, m),4.05 (2H, m), 4.35 (2H, q, J=7 Hz), 8.35 (1H, s), 8.70 (1H, s), 9.10(1H, t, exchanged with D₂ O).

EXAMPLE 7 7-Allylamino-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acidallyl amide (E7) ##STR26##

A solution of ethyl 7chloro-1H-pyrazolo[4,3-b]-pyridine-5-carboxylate(1.5 g, 6.65 mmol) in allylamine (25 ml) was heated under reflux for 3days. The solvent was evaporated in vacuo and the residue was extractedinto warm ether to give 7-chloro-1H-pyrazolo[4,3-b]pyridine-5-carboxylicacid allyl amide as a pale yellow solid, m.p. 121°-125° C. Withoutfurther purification, this material was dissolved in allylamine (10 ml)and water (10 ml) and heated under reflux for 6 days. Excess allylaminewas removed in vacuo and the precipitated solid was collected and washedwell with water, to give the crude product (940 mg, 55%).Recrystallisation from ethyl acetate gave the title compound, m.p.194°-197° C.

δ(DMSOd₆): 3.85 (2H, t), 4.12 (2H, t), 4.95-5.45 (4H, m), 5.50-6.20 (5H,m), 7.25 (1H, s), 8.17 (1H, s), 8.40 (1H, t, exchanged with D₂ O).

EXAMPLE 8 Ethyl 7-Allylamino-1H-pyrazolo[4,3-b]pyridine-5-carboxylate(E8) ##STR27##

A suspension of 7-allylamino-1H-pyrazolo[4,3-b]-pyridine-5-carboxylicacid allylamide (500 mg, 1.94 mmol) in ethanolic hydrogen chloride (15ml) was heated under reflux for 5 days with periodic addition of smallaliquots of ethanolic hydrogen chloride. The solvent was evaporated invacuo and the residue was dissolved in warm aqueous ethanol. Thesolution was adjusted to pH 8 with aqueous sodium carbonate solution,and after evaporation of excess ethanol, the product (170 mg, 37%) wascollected and washed well with water. Recrystallisation fromethanol/ether gave the title compound, m.p. 140°-145° C.

δ(DMSO-d₆): 1.35 (3H, t, J=7 Hz), 4.05 (2H, m), 4.35 (2H, q, J=7 Hz),5.00-5.50 (2H, m), 5.57-6.30 (1H, m), 7.05 (1H, s), 7.05 (1H, bs,exchanged with D₂ O), 8.30 (1H, s), 13.00 (1H, bs, exchanged with D₂ O).

EXAMPLE 9 7-Anilino-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid anilide(E9) ##STR28##

A solution of ethyl 7-chloro-1H-pyrazolo [4,3-b]-pyridine-5-carboxylate(1.2 g, 5.3 mmol) in aniline (10 ml) was heated under reflux undernitrogen for 24 h. The mixture was cooled, diluted with ethyl acetate,and the precipitated product was collected. Column chromatography onsilica, eluting with 5% methanol/ethyl acetate gave the title compoundwhich was recrystallised from ethyl acetate to give a white solid (0.57g, 33%) mp 248°-250° C.

δ (DMSO-d₆) 6.95-7.6 (9H, m), 7.70 (1H, s), 7.85 (2H, dd, J=7, 2 Hz),8.35 (1H, s), 8.90 (1H, br s, exchanges with D₂ O), 10.50 (1H, br s,exchanges with D₂ O).

EXAMPLE 10 Ethyl 7-Anilino-1H-pyrazolo[4,3-b]pyridine-5-carboxylate(E10) ##STR29##

The title compound was prepared by the method of Example 8 as a paleyellow solid (47%) mp. 230°-234° C.

δ (DMSO d₆) 1.30 (3H, t, J=7 Hz), 4.30 (2H, q, J=7 Hz), 7.0-7.55 (5H,m), 7.60 (1H, s), 8.40 (1H, s), 8.93 (1H, s, exchanges with D₂ O), 12.90(1H, br s, exchanges with D₂ O).

EXAMPLE 11 Ethyl7-allylamino-2-methyl-pyrazolo[4,3-b]pyridine-6-carboxylate (E11)##STR30##

The above compound was prepared from ethyl7-chloro-2-methyl-pyrazolo[4,3-b]pyridine and n-allylamine in ananalogous manner to the preparation of Example 2 to give a white solid,m.p. 140°-143° C.

δ (CDCl₃) 1.39 (3H, t, J=7 Hz), 4.10 (3H, s), 4.28 (2H, q, J=7 Hz),4.6-5.45 (4H, m), 5.75-6.45 (1H, m), 7.80 (1H, s), 8.70 (1H, s).

EXAMPLE 12 7-Isobutylamino-1H-5-trifluoromethylpyrazolo-[4,3-b]pyridine(E12) ##STR31##

7-Chloro-1H-5-trifluoromethylpyrazolo[4,3-b]pyridine (D6) (0.24 g) iniso-butylamine (5 ml) was heated at reflux for 2 days and thenevaporated to dryness. The residue was chromatographed on silica gelwith ether as eluant to give a white crystalline solid. The solid wastaken up in a small volume of methanol and water added. The solution wasbrought to pH 8 with aqueous ammonia. The resulting white solid, therequired free base, was collected, washed with water and dried, m.p.194°-196° C.

(Found: C, 51.14; H, 5.20; N, 21.91. C₁₁ H₁₃ F₃ N₄ requires C, 51.16; H,5.06; N, 21.70%)

δ (DMSO-d₆) 1.01 (6H, d, J=6 Hz), 1.6-2.3 (1H, m), 3.05-3.35 (2H, m),6.67 (1H, s), 6.94 (1H, br.t, exchanges with D₂ O), 8.25 (1H, s), 13.05(1H, br.s, exchanges with D₂ O).

Found M+ 258.1089. C₁₁ H₁₃ F₃ N₄ requires 258.1092.

PHARMACOLOGICAL DATA Mouse Oxazolone Screen

Compounds were tested for topical anti-inflammatory activity in a screenusing the mouse sensitised to oxazolone, by a method modified from thatof Dietrich and Hess [Dietrich, F. M., and Hess, R., Int. Arch. Allergy,(1970), 38, 246-259].

Mice were sensitised with oxazolone (2 mg in 20 μl ethanol) on a shavedarea of the abdomen. Five days later, the animals recieved 10 μlTHF/MeOH (1:1 v/v) on the right ear, and the test compound in the samesolvent on the left ear. One hour later, the animals were challengedwith 100 μg oxazolone in 10 μl acetone on each ear. Ear weights weremeasured 24 h later. Percentage inhibition of the inflammatory swellingrefers to the increase in weight of left ears (oxazolone plus compound)compared with solvent-treated negative controls, as a proportion of theincrease in weight of right ears (oxazolone alone) over similarcontrols.

In this test the compound of Example 1 had an inhibition of 24% at adose of 500 μg/ear.

Mouse Cantharidin Screen

Compounds were tested for topical anti-inflammatory activity in acantharidin mouse ear screen, modified from Swinge et al [Swingle, K.F., Reiter, M. J. and Schwartzmiller, D. H., Arch. Int. Pharmacodyn.,(1981), 254, 168-176].

25 μg cantharidin (in 10 μl THF/MeOH) was applied to both ears.Compound, in the same solvent, was applied at the same time, to the leftear only. Ears were weight 24 h after cantharidin application.Percentage inhibition of the acute inflammatory swelling refers to theincrease in weight of left ears (cantharidin plug compound) comparedwith solvent-treated negative controls, as a proportion of the increasein weight of right ears (cantharidin alone) over similar controls.

In this test the compound of Example 6 gave an inhibition of 42% at 200μg/ear and the compound of Example 2 gave an inhibition of 20% at a doseof 500 μg/ear.

RBL-1 5-Lipoxygenase Screen

5-Lipoxygenase enzyme was prepared as a 10,000 g supernatant from RBL-1cells by the method of Jakschik [Jakschik, B. A., Sun. F. F., Lee, L. M.and Steinhoff, M. M., 1980, Biochem. Biophys. Res. Comm. 95, 103]. The10,000 g supernatant was diluted with homogenization buffer to theequivalent of 1.5-2.5×10⁷ cells ml⁻¹ and made 2 mM with respect toCaCl₂. Aliquots of 0.5 ml were then dispensed into tubes, and incubatedat 29° C. with 5 γl ethanol or compound in ethanol at the desiredconcentration for 2 min. Then [1-¹⁴ C] arachidonic acid was added inbuffer to give a final concentration of 6.3 μm and 0.2 μCi perincubation, and the reaction continued at 29° C. for 2 min. The reactionwas terminated by adding 1 ml of acetone and cooling on ice, 0.5 ml ofice-cold saline and 10 μl of 2N formic acid were added, and the mixturewas extracted with 2×2 ml of chloroform. The extract was stored under N₂at -20° C. until analysis by chromatography. Activity was measured asthe percentage of total radioactivity found in 5-HETE and 5,12-diHETE,and inhibition calculated as the decrease in formation of the sum ofthese two species in compound-treated incubates relative to controlincubates.

In this test the compound of Exampble 6 gave an inhibition of 78% at 20μM.

We claim:
 1. A compound of formula (I) or a pharmaceutically acceptablesalt thereof: ##STR32## wherein: X is sulphur SO or NR wherein R ishydrogen of C₁₋₆ alkyl, SO₂ ;R₁ is COR₅ wherein R₅ is hydroxy, C₁₋₆alkoxy, C₂₋₆ alkenyloxy, phenoxy or benzyloxy wherein the phenyl andbenzyl moieties are optionally substituted by one or two of halogen,CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or R₅ is NR₁₃ R₁₄ wherein R₁₃ and R₁₄are independently hydrogen, C₂₋₋₆ alkyl, C₂₋₋₆ alkenyl, benzyl or phenylwherein the phenyl and benzyl moieties are optionally substituted by oneor two of halogen, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or CF₃ ; and R₂ ishydrogen, C₁₋₋₆ alkyl or phenyl optionally substituted by halogen, CF₃,C₁₋₋₄ alkoxy or C₁₋₋₄ alkyl; or R₂ is COR₅ as defined above or CF₃ andR₁ is hydrogen; R₃ is C₁₋₋₁₀ alkyl, optionally substituted by hydroxy,C₁₋₋₄ alkoxy, thiol, C₁₋₋₄ alkylthio or NR₆ R₇ wherein R₆ and R₇ areindependently hydrogen or C₁₋₋₆ alkyl or together are C₃₋₋₆polymethylene; C₂₋₋₁₀ alkenyl or phenyl optionally substituted by one ortwo halogen, CF₃, C₁₋₋₄ alkoxy, C₁₋₋₄ alkyl, hydroxy, nitro, cyano,C₂₋₋₁₀ carboxylic acyloxy, NR₈ R₉ wherein R₈ and R₉ are independentlyselected from hydrogen, C₁₋₋₆ alkyl, C₂₋₋₇ alkanoyl or C₁₋₋₆alkylsulphonyl or COR₁₀ wherein R₁₀ is hydroxy, C₁₋₋₆ alkoxy or NR₁₁ R₁₂wherein R₁₁ and R₁₂ are independently selected from hydrogen or C₁₋₋₆alkyl; and R₄ is hydrogen; or C₁₋₋₄ alkyl or benzyl attached at nitrogenatom 1 or
 2. 2. A compound according to claim 1 of formula (III):##STR33## wherein R₁ ¹ is COR₅ ¹, wherein R₅ ¹ is hydroxy C₁₋₋₆ alkoxy,C₂₋₋₆ alkenyloxy, phenoxy or benzyloxy wherein the phenyl and benzylmoieties are optionally substituted by one or two of halogen, CF₃, C₁₋₋₄alkoxy and C₁₋₋₄ alkyl; or R₅ ¹ is NR₁₃ R₁₄ wherein R₁₃ and R₁₄ areindependently hydrogen, C₂₋₋₆ alkyl, C₂₋₋₆ alkenyl, benzyl or phenylwherein the phenyl and benzyl moieties are optionally substituted by oneor two of halogen, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or R₁ ¹ is CF₃, R'is hydrogen or methyl, R₄ ¹ is hydrogen or 2-methyl, and R₃ is asdefined in claim
 1. 3. A compound according to claim 2 of formula (IV):##STR34## wherein R₁₅ is hydrogen, chloro, bromo, methoxy, ethoxy,hydroxy, cyano, carboxyl, ethoxycarbonyl, nitro or t-butyl.
 4. Acompound according to claim 2 of formula (V): ##STR35## wherein R₃ ¹ isn-butyl, n-pentyl, allyl, 2-methylallyl, 2-hydroxyethyl,3-hydroxypropyl, 2-thiolethyl, 2-methoxyethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 2-pyrrolidinoethyl 3-pyrrolidinopropyl and R₁ ¹and R₄ ¹ are as defined in claim
 2. 5. A compound according to claim 1of formula (VI): ##STR36## wherein R₂ ¹ is COR₅ ¹ wherein R₅ ¹ ishydroxy, C₁₋₋₆ alkoxy, C₂₋₋₆ alkenyloxy, phenoxy or benzyloxy whereinthe phenyl and benzyl moieties are optionally substituted by one or twoof halogen, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or R₅ ¹ is NR₁₃ R₁₄wherein R₁₃ and R₁₄ are independently hydrogen, C₂₋₋₆ alkyl, C₂₋₋₆alkenyl, benzyl or phenyl wherein the phenyl and benzyl moieties areoptionally substituted by one or two of halogen, CF₃, C₁₋₋₄ alkoxy andC₁₋₋₄ alkyl;R' is hydrogen or methyl; R₄ ¹ is hydrogen or 2-methyl; andR₃ is C₁₋₋₁₀ alkyl, optionally substituted by hydroxy, C₁₋₋₄ alkoxy,thiol, C₁₋₋₄ alkylthio or NR₆ R₇ wherein R₆ and R₇ are independentlyhydrogen or C₁₋₋₆ alkyl or together are C₃₋₋₆ polymethylene; C₂₋₋₁₀alkenyl or phenyl optionally substituted by one or two of halogen, CF₃,C₁₋₋₄ alkoxy, C₁₋₋₄ alkyl, hydroxy, nitro, cyano, C₂₋₋₁₀ carboxylicacyloxy, NR₈ R₉ wherein R₈ and R₉ are independently selected fromhydrogen, C₁₋₋₆ alkyl, C₂₋₋₇ alkanoyl or C₁₋₋₆ alkylsulphonyl or COR₁₀wherein R₁₀ is hydroxy, C₁₋₋₆ alkoxy or NR₁₁ R₁₂ wherein R₁₁ and R₁₂ areindependently selected from hydrogen or C₁₋₋₆ alkyl.
 6. A compoundaccording to claim 5 of formula (VII): ##STR37## wherein R₃ ¹ isn-butyl, n-pentyl, allyl, 2-methylallyl, 2-hydroxyethyl,3-hydroxypropyl, 2-thioethyl, 2-methoxyethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 2-pyrrolidinoethyl, or 3-pyrrolidinopropyl and R₄¹ is hydrogen or 2-methyl and R₂ ¹ is COR₅ ¹ wherein R₅ ¹ is hydroxy,C₁₋₋₆ alkoxy, C₂₋₋₆ alkenyloxy, phenoxy or benzyloxy wherein the phenyland benzyl moieties are optionally substituted by one or two of halogen,CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or R₅ ¹ is NR₁₃ R₁₄ wherein R₁₃ andR₁₄ are independently hydrogen, C₂₋₋₆ alkyl, C₂₋₋₆ alkenyl, benzyl orphenyl wherein the phenyl and benzyl moieties are optionally substitutedby one or two of halogen, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl.
 7. Acompound selected from the group consisting ofethyl7-anilino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate, ethyl7-Allylamino-1H-pyrazolo[4,3-b]-pyridine-6- carboxylate, ethyl7-(4-Hydroxyanilino)-1H-pyrazolo[4,3-b]pyridine-6-carboxylate, ethyl7-Amylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate, ethyl7-Phenylthio-1H-pyrazolo[4,3-b]pyridine-6-carboxylate, ethyl7-n-Butylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate,7-allylamino-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid allyl amide,ethyl 7-Allylamino-1H-pyrazolo[4,3-b]pyridine-5-carboxylate,7-anilino-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid anilide, ethyl7-Aniliono-1H-pyrazolo[4,3-b]pyridine-5- carboxylate, ethyl7-allylamino-2-methyl-pyrazolo [4,3-b]pyridine-6-carboxylate and7-isobutylamino-1H-5-trifluoromethylpyrazolo-[4,3-b]pyridine.
 8. Apharmaceutical composition for the treatment of inflammatory or allergicconditions comprising an effective amount of a compound of formula (I):##STR38## wherein: X is oxygen, sulphur, SO or SO₂ or NR wherein R ishydrogen or C₁₋₋₆ alkyl;R₁ is COR₅ wherein R₅ is hydroxy, C₁₋₋₆ alkoxy,C₂₋₋₆ alkenyloxy, phenoxy or benzyloxy wherein the phenyl and benzylmoieties are optionally substituted by one or two of halogen, CF₃, C₁₋₋₄alkoxy and C₁₋₋₄ alkyl; or R₅ is NR₁₃ R₁₄ wherein R₁₃ and R₁₄ areindependently hydrogen, C₂₋₋₆ alkyl, C₂₋₋₆ alkenyl, benzyl or phenylwherein the phenyl and benzyl moieties are optionally substituted by oneor two halogens, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl; or CF₃ ; and R₂ ishydrogen, C₁₋₋₆ alkyl or phenyl optionally substituted by halogen, CF₃,C₁₋₋₄ alkoxy or C₁₋₋₄ alkyl; or R₂ is COR₅ as defined above or CF₃ andR₁ is hydrogen; R₃ is C₁₋₋₁₀ alkyl, optionally substituted by hydroxy,C₁₋₋₄ alkoxy, thiol, C₁₋₋₄ alkylthio or NR₆ R₇ wherein R₆ and R₇ areindependently hydrogen or C₁₋₋₆ alkyl or together are C₃₋₋₆polymethylene; C₂₋₋₁₀ alkenyl or phenyl optionally substituted by one ortwo halogen, CF₃, C₁₋₋₄ alkoxy, C₁₋₄ alkyl, hydroxy, nitro, cyano, C₂₋₁₀carboxylic acyloxy, NR₈ R₉ wherein R₈ and R₉ are independently selectedfrom hydrogen, C₁₋₋₆ alkyl, C₂₋₋₇ alkanoyl or C₁₋₋₆ alkylsulphonyl orCOR₁₀ wherein R₁₀ is hydroxy, C₁₋₋₆ or NR₁₁ R₁₂ wherein R₁₁ and R₁₂ areindependently selected from hydrogen or C₁₋₋₆ alkyl; and R₄ is hydrogen;or C₁₋₋₄ alkyl or benzyl attached at nitrogen atom 1 or 2; or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 9. A method of treatment of inflammatory or allergicconditions in mammals comprising the adminstration of an effectiveamount of a compound of formula I: ##STR39## wherein: X is oxygen,sulphur, SO or SO₂ or NR wherein R is hydrogen or C₁₋₋₆ alkyl;R₁ is COR₅wherein R₅ is hydroxy, C₁₋₋₆ alkoxy, C₂₋₋₆ alkenyloxy, phenoxy orbenzyloxy wherein the phenyl and benzyl moieties are optionallysubstituted by one or two of halogen, CF₃, C₁₋₋₄ alkoxy and C₁₋₋₄ alkyl;or R₅ is NR₁₃ R₁₄ wherein R₁₃ and R₁₄ are independently hydrogen, C₂₋₋₆alkyl, C₂₋₋₆ alkenyl, benzyl or phenyl wherein the phenyl and benzylmoieties are optionally substituted by one or two of halogen, CF₃, C₁₋₋₄alkoxy and C₁₋₋₄ alkyl; or CF₃ ; and R₂ is hydrogen, C₁₋₋₆ alkyl orphenyl optionally substituted by halogen, CF₃, C₁₋₋₄ alkoxy or C₁₋₋₄alkyl; or R₂ is COR₅ as defined above or CF₃ and R₁ is hydrogen; R₃ isC₁₋₋₁₀ alkyl, optionally substituted by hydroxy, C₁₋₋₄ alkoxy, thiol,C₁₋₋₄ alkylthio or NR₆ R₇ wherein R₆ and R₇ are independently hydrogenor C₁₋₋₆ alkyl or together are C₃₋₋₆ polymethylene; C₂₋₋₁₀ alkenyl orphenyl optionally substituted by one or two halogen, CF₃, C₁₋₋₄ alkoxy,C₁₋₋₄ alkyl, hydroxy, nitro, cyano, C₂₋₋₁₀ carboxylic acyloxy, NR₈ R₉wherein R₈ and R₉ are independently selected from hydrogen, C₁₋₋₆ alkyl,C₂₋₋₇ alkanoyl or C₁₋₋₆ alkylsulphonyl or COR₁₀ wherein R₁₀ is hydroxy,C₁₋₋₆ alkoxy or NR₁₁ R₁₂ wherein R₁₁ and R₁₂ are independently selectedfrom hydrogen or C₁₋₋₆ alkyl; and R₄ is hydrogen; or C₁₋₋₄ alkyl orbenzyl attached at nitrogen atom 1 or 2; or a pharmaceuticallyacceptable salt thereof to the sufferer.